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Allergies and Autoimmune Disorders in Children After Heart

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Allergies and Autoimmune Disorders in Children After Heart DR. NICHOLAS AVDIMIRETZ (Orcid ID : 0000-0002-7108-3785) Article type : Original Article TITLE Allergies and Autoimmune Disorders in Children after Heart Transplantation RUNNING TITLE Allergies in Pediatric Heart Transplantation AUTHORS Nicholas Avdimiretz, MD, FRCPC 1,2 Stefanie Seitz, MD 3 Tiffany Kim, BSc 1 Faye Murdoch, RN 1,4 Simon Urschel, MD, FRCPC 1,4,5 Article AFFILIATIONS 1 Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Canada 2 Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada 3 University of Heidelberg, Heidelberg, Germany 4 Alberta Transplant Institute, University of Alberta, Edmonton, Canada 5 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada ACKNOWLEDGMENTS We would like to thank the Pediatric Cardiac Transplant team at the Stollery Children’s Hospital for their contributions to this work. Research has been funded by the Women’s and Children’s Health Research Institute (WCHRI), Alberta, Canada. CORRESPONDING AUTHOR Nicholas Avdimiretz, MD: Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8; Phone: +1-416-813-1500; Email: [email protected] CONFLICT OF INTEREST STATEMENT The authors do not have any conflicts of interest to disclose. ABSTRACT Pediatric heart transplantation requires lifelong immune suppression and may require thymectomy, both of which alter T-cell repertoires. We hypothesized that atopic and autoimmune diseases are more common in pediatric heart transplant patients than the general population, and that transplantation in early childhood increases the risk of development or worsening of atopic or autoimmune disease. This article has been accepted for publication and undergone full peer review but has not Accepted been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ctr.13400 This article is protected by copyright. All rights reserved. A cross-sectional single-centre study including 21 heart transplant patients aged ≤ 18 years was conducted. Data collected included age at transplant, induction, thymectomy, and development and severity of atopic or autoimmune disease. A majority (67%) reported having any atopic disease post- transplant, all of whom reported onset or worsening post-transplantation. Thymectomized patients were significantly more likely to have asthma (p=0.018) and report asthma worsening post-transplant (p=0.045). Patients with worsening of asthma post-transplant were transplanted at a significantly younger age (p=0.040). ABO incompatible and ABO compatible recipients presented similarly. Anemia was common (38%) but not always clearly of autoimmune origin. Atopic diseases are common in children following heart transplantation: compared to the general population, there is a higher prevalence of eczema (43% versus 11%) and asthma (33% versus 9%). Article Both thymectomy and younger age at transplant are associated with atopic disorders, possibly due to altered T-cell repertoires. KEYWORDS Pediatric heart transplantation, allergies, autoimmune disorders, immune suppression, induction, thymectomy INTRODUCTION Heart transplantation is a life-saving intervention in infants and children with end-stage heart failure or congenital heart disease without promising surgical treatment. In order to prevent rejection, patients who have undergone cardiac transplantation require life-long suppression of the immune system. This may include intense induction therapy at the time of transplant with polyclonal anti-lymphocyte antibodies (anti-thymocyte globulin, ATG), resulting in subtotal depletion of lymphocytes, including mature and memory T- and B-cells. In the course of transplant or pre-transplant surgeries, incidental thymectomy to improve exposure of the operating field is commonly performed. The thymus is an essential organ for the maturation of bone-marrow derived precursor cells into a diverse pool of new effector and regulatory T-lymphocytes, and is a key structure in the development of self-tolerance. Accepted The combination of T-cell depletion by induction and removal of a key organ for regeneration of This article is protected by copyright. All rights reserved. these cells may have profound impact on the recipient’s immunological competence and ability to differentiate self from foreign. A role of age and maturity of the immune system on incidence, prevalence, and type of manifestation of autoimmune and allergic disorders has previously been recognized in children with healthy immune systems. Accordingly, the timing of manipulation of the immune system via transplantation and immune suppression may influence the development of allergic and autoimmune disorders. Allergic diseases such as allergic rhinoconjunctivitis, asthma, and atopic dermatitis have repeatedly been observed in patients after solid organ transplantation. In pediatric kidney, liver, and lung transplant recipients, the prevalence of type I sensitization to allergens was found in comparable numbers to the general population regardless of the type of transplanted organ [1,2,3,4]. There are a Article number of case reports of pediatric patients developing food allergies after solid organ transplantation, particularly in patients following liver transplantation versus any other solid organ transplant [5,6,7]. However, our clinical experience indicates that allergic manifestations are very common in heart transplanted children. A number of studies have shown that thymectomy in infants and older children results in alterations of the peripheral T-cell compartment, including CD4+ and CD8+ T-lymphocytes [8,9] and regulatory T-cells [10]. The most prominent alterations seem to come with young age and early sampling post- thymectomy [11]. Thymectomy also results in premature senescence of the T-cell segment reflected in lower proportions of recent thymic emigrant cells and decreased levels of T-cell receptor excision circles (TREC), a marker for thymopoiesis in the blood [9,12]. The combination with T-cell depleting induction likely enhances these effects [13,14,15]. We hypothesized that the combination of removal of the thymus in cardiac transplant recipients, along with the treatment of T-cell depleting agents results in significant immune dysregulation, thereby increasing the likelihood of allergic and autoimmune disorders post-transplantation. With this study, Accepted This article is protected by copyright. All rights reserved. we sought to determine the incidence of these disorders in our patients and the role of potential additional risk factors such as thymectomy and younger age at transplant. MATERIALS AND METHODS We conducted a cross-sectional study of pediatric heart transplant patients aged ≤ 18 years seen at the Stollery Children’s Hospital between 2013 and 2015. Institutional ethics approval was obtained. All pediatric heart transplant recipients were offered participation in the study, and consent and assent were obtained by the legal guardian and patient, respectively. Data were collected by (1) review of medical records and (2) standardized face-to-face or telephone survey. Data collected included demographics, underlying cardiac diagnosis, age at transplant, use and type of induction therapy, blood group (ABO) compatibility, development and severity of atopic or autoimmune disease, and Article family history of atopy and autoimmunity. Atopic or autoimmune disease was defined as being physician-diagnosed. Data obtained from patient interview was cross-referenced with medical records to ensure diagnostic accuracy. Allergic diseases, including but not limited to eczema, asthma, atopic urticaria, and food allergy were included; in addition to a variety of autoimmune diseases including type 1 diabetes mellitus and inflammatory bowel disease [Table 1]. Severity of disease was classified on a nominal scale from 0 to 3: 0 was defined as no diagnosis or problem, 1 was defined as “mild” disease leading to no impairment of activities, 2 was defined as “moderate” disease leading to some impairment (impairment of certain activities while still able to lead a normal life), and 3 was defined as “severe” with significant impairment to daily life. Removal of the thymus was documented in operative notes, although inconsistently documented ≤ 12 months of age. This is because removal as a whole was the standard approach of the cardiac surgeons for patients ≤ 12 months of age at our institution in the observed time frame; therefore thymectomy was presumed for transplants or pre- transplant cardiac surgeries occurring ≤ 12 months of age. Statistical analysis consisted of descriptive statistics, and comparison of dependent variables using the Fisher’s exact test for categorical data and Mann-Whitney U test for quantitative data. Accepted This article is protected by copyright. All rights reserved. RESULTS Out of 35 pediatric heart transplant patients meeting inclusion criteria, 21 were recruited into the study. Main reason for non-recruitment was unwillingness to participate in the study. Time from transplant date to study date was highly variable, averaging at 4.6 years. Demographics and clinical background are outlined in Table 2. None of the included patients had any detected genetic disorder affecting the immune system: including 22q11 microdeletion, trisomy 21, or congenital primary immunodeficiency. Indication
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